Neurons communicate by sending excitatory and inhibitory signals. Not surprisingly, numerous disorders of the nervous system are associated with a disturbance in the balance between these signals, producing either too much or too little activity. A classic example of imbalanced excitation and inhibition is the neural hyperexcitability found in epilepsy, a common disorder characterized by a propensity of neurons to fire in excessive synchrony, resulting in seizures. Much is known about the cellular biophysics and neural networks that contribute to epilepsy in animal models;however, less is known about mechanisms of human epilepsy. The proposed experiments will use state-of-the-art, multi-modal neuroimaging techniques to study neural hyperexcitability in patients with idiopathic generalized epilepsies. The experiments will combine visual stimulation paradigms and a computational framework based on current "normalization" models of sensitivity regulation in the visual system as a novel approach for understanding the pathophysiological mechanisms of epilepsy. Brain responses of patients with epilepsy will be studied with a combination of electrocephalography (EEG) and functional magnetic resonance imaging (fMRI) techniques. The use of visual stimulation will allow for precise manipulation of inputs to the brain and multi-modal functional imaging will allow the measurement of brain responses with high spatial and temporal resolution. In Aim 1, the balance of inhibition and excitation will be studied in cortical visual areas using a visual masking paradigm. EEG source imaging will be used to address the nature and cortical site of hyperexcitability. In Aim 2, high resolution fMRI will be used to measure visual responses in the lateral geniculate nucleus of the thalamus to determine if this structure participates in the epileptic brain network. In Aim 3, visual responses around the time of occurrence of epileptiform brain activity will be examined for premonitory patterns in the transition from normal to abnormal brain activity. The results of these studies not only have implications for developing novel treatment and biomarkers for diagnosis and management of epilepsy, but the methods developed can be applied to other brain disorders of altered neural excitation/inhibition and be extended to other sensory modalities. Outstanding resources and mentorship are available at the Smith-Kettlewell Eye Research Institute and at UCSF in the Epilepsy Center. Drawing on these resources, this proposal will combine training in advanced neuroimaging techniques and clinical research experience to allow the candidate to meet his career goal: to explore the basis of electrophysiological disorders of the human brain in order to improve the well-being of patients. PUBLIC HEALTH RELEVANCE: Epilepsy is a common neurological disorder that affects almost 3 million Americans at an annual cost of about $15.5 billion. This proposal will contribute to the identification of the basic mechanisms of seizure generation that will lead to the development of cures and of tools that will validate such cures.